Summary: Hepatitis B virus (HBV) is a small DNA virus that chronically infects 240 million people worldwide, resulting in over 650 thousand deaths annually. HBV-induced fatalities typically result from a variety of severe liver pathologies including cirrhosis, hepatocellular carcinoma and liver failure. The current standard of care for chronic HBV infection uses viral DNA polymerase inhibitors or immunomodulators (interferons) that reduces viral loads and prevents progression of liver disease, but rarely induces a functional cure, with recurrence occurring nearly universally following cessation of treatment. The failure to achieve a functional cure is attributed to the persistence of viral covalently closed circular DNA (cccDNA) pools in infected liver cells that is neither suppressed nor eliminated by these therapies. Accordingly, there is a critical need for new HBV therapeutics targeting multiple stages of the viral lifecycle which can affect these cccDNA pools. We have discovered a new Type of HBV core protein allosteric modulators (CpAMs), exemplified by MBX-6035, that disrupt capsid assembly through a unique phenotype. Analysis of MBX-6035 analogs revealed responsive SAR and included analogs that are potent (EC50 as low as 1.3 M), selective (>100-fold SI), soluble (up to 400 M), minimally protein bound (>30% unbound in murine plasma), and metabolically stable (t1/2 >100 min in murine liver microsomes), strongly justifying further pursuit of this novel series. Our strategy in this Phase I proposal is to optimize the potency and drug-like properties of this series to generate lead compounds suitable for further development and demonstration of in vivo efficacy in a future Phase II application.